Senile dementia has recently been recognized as a degenerative central nerve system disorder. The number of patients suffering from the disease has been increased to become a serious social problem, and so the prevention, amelioration, and treatment of the disease are now considered very important.
Alzheimer's disease, vascular diseases, Parkinson's disease, hypothyroidism, and alcoholic dementia are known as disorders which may cause dementia, but more than 50% of the patients suffering from senile dementia are found to suffer from Alzheimer's disease. The central nerve system of the patients suffering from Alzheimer's disease is generally impaired, and particularly, cholinergic neuron is most severely impaired. Thus, the studies to develop therapeutic agents to improve cholinergic neuronal functions have been vigorously conducted.
A method to improve the functions of impaired cholinergic neuron is to administer cholinergic receptor agonist or acetylcholinesterase (AChE) inhibitor to inhibit degradation of acetylcholine (ACh), a cholinergic neurotransmitter, and thereby to maintain the concentration of synaptic ACh.
However, cholinergic receptor agonist has a disadvantage to be readily degraded in vivo, and thus, AChE inhibitor is generally used. That is, AChE inhibitor ameliorates the conditions of senile dementia by preventing the degradation of AChE by inhibiting the activity of AChE, an enzyme to degrade ACh, and maintaining the concentration of synaptic Ach, and thereby sustaining a series of cholinergic receptor-mediated reactions.
This is supported by the fact that most of the drugs that have been developed as therapeutic agents for Alzheimer's disease and currently on clinical use or trial are AChE inhibitors. AChE inhibitors that have been approved by the United States Food and Drug Administration and used as therapeutic agents of dementia are exemplified by tacrine (THA, Cognex®), donepezil (Aricept®), rivastigmaine (Exelon®), and galanthamine (Reminyl®) that is most recently approved. However, these AChE inhibitors are known to have such problems as hepatotoxicity, short half-life, low bioavailability, etc. Thus, more studies have been performed to develop a novel AChE inhibitor.
The present inventors have tested various natural products for AChE inhibitory activity to identify the activity with using in vivo experimental models by finding a substance with AChE inhibitory activity from the natural products that have been used as traditional Korean folk medicines for a long time. As a result, the present inventors found out that a methanolic extract of Angelicae gigantis Radix has significant AChE inhibitory activity and cognition-enhancing activity.
Angelicae gigantis Radix is an herbal medicine used as a sedative, an analgesic, or a tonic agent, and particularly an essential drug used after childbirth for anemia and women's diseases, etc. by sedative and menstruation-promoting actions. In Korea, the dried root of Angelica gigas Nakai has been used as Angelicae gigantis Radix.
Further, the present inventors isolated and purified active ingredients showing AChE inhibitory and cognition-enhancing activities from Angelicae gigantis Radix, and synthesized many compounds by using the active ingredients as starting materials and tested them for their cognition-enhancing activity. As a result, they found out pyranocoumarin derivatives of the general formula (I) have cognition-enhancing activity. Therefore, the present inventors completed the present invention.